Thiazides are extensively prescribed for hypertensive and/or diuretic therapy because of their profound effect and minor tolerance development. The hypokalemia that frequently develops with chronic administration has been implicated in the pathogenesis of dysrhythmias, digitalis toxicity, myocardial ischemia and sensitization of the heart to catecholamine-induced necrosis. The overall hypothesis of the proposed research is that there is an accentuation of the norepinephrine-induced myocardial necrosis by thiazide treatment which is mediated by changes in potassium (K ion) and Calcium (Ca ions) ions in anesthetized, open chested dogs. The first phase involves the acute effects of varying doses of norepinephrine (NE) infusions for one hour on: 1) plasma and tissue levels of K ion and Ca ions, 2) membrane permeability as measured with horseradish peroxidase, 3) quantitative histopathological changes in the production of "contraction band" lesions, 4) qualitative ultrastructural changes in the two types of "contraction band" lesions and 5) intracellular accumulation and redistribution of calcium in these necrotic cells. The second phase will examine whether there is any accentuation in these same parameters in hearts that have been chronically treated with a clinical or pharmacological dose of chlorothiazide. To test whether the suspected accentuation of necrosis is mediated by hypokalemia, the third phase will examine this spectrum of parameters in K ion - depleted hearts produced by dietary reductions alone. The final phase will examine the potential protective effects of K ion replenishment in chlorothiazide-induced K ion - depletion prior to NE infusions. Documentation of a possible synergistic effect of thiazides and catecholamine stress is vital in light of the large number of hypertensive patients and the widespread use of thiazides in their treatment.